The cardiopulmonary failure that accompanies serious illness is thought to be mediated or intensified by activated platelets and leukocytes (WBCs) that are entrapped in the lungs, releasing agents that control bronchopulmonary smooth muscle tone and alter permeability. The role of thromboxane (Tx) A2 and prostacyclin (PGI2) will be emphasized since these prostanoids may directly affect cardiopulmonary function as well as exert indirect control by influencing platelet and WBC aggregation and release of vasoactive and vasotoxic agents. The double antibody radioimmunoassay will be used to quantitate the TxA2 and PGI2 response to putative regulatory stimuli: pulmonary hypoxia, systemic ischemia, products of clotting and lysis, platelet secretions, angiotensin II, and mechanical deformation. Platelet and WBC activation and release will be examined using: aggregometry and assay of cellular and plasma products such as TxB2, serotonin (5-HT), cathepsins, superoxides, and leukotrienes. We will investigate the surprising ability of PGI2 to either inhibit or stimulate platelet TxA2 synthesis and the effect of PGI2 on platelet-endothelial 5-HT transport. Experimental preparations in dogs and sheep that lead to platelet and combined platelet-WBC sequestration in the lungs, pulmonary embolism and acid aspiration respectively, will be used to examine the role of each cell type. Our approach will be to render some animals thrombocytopenic while others will have platelets and WBCs labeled with 51Cr and 111In. The sequence of cell entrapment, change in lymph, plasma and platelet prostanoid and 5-HT concentration will be related to cardiopulmonary function. Since we believe the earliest mediators of organ dysfunction prior to pulmonary edema are 5-HT and TxA2 the action of selective antagonists will be studied. WBC mediated microvascular permeability with possible amplification by platelets or their secretions will also be explored. The ability of imidazole and its analogues to inhibit WBC synthesis and/or release of permeability factors will be tested ex-vivo and in animals. Finally, selective 5-HT and Tx synthetase inhibitors and PGI2 itself will be employed in clinical setting where platelets, WBCs or both cell types are activated in order to evaluate the functional importance of these cells and their secretions.